Mycobacterium tuberculosis is the etiologic agent of tuberculosis which remains the leading cause of mortality due to an identifiable infectious agent worldwide. Most individuals successfully contain a primary infection and develop a vigorous delayed-type hypersensitivity (DTH) response to mycobacterial antigens. T. cells are thought to play a critical role in the immune response which follows infection with M. tuberculosis. They mediate and regulate the acquired immune response which controls primary infection and provides protection against exogenous reinfection. Failure of the T cell response contributes to progressive primary infection and to reactivation of endogenous foci of mycobacteria. Based on studies in humans and animal models, the CD4+ T cell traditionally has been considered the main T cell subset responsible for regulating the protective immune response to M. tuberculosis. Studies by us (supported by AI27243) and others, however, have demonstrated that the CD4+ T cell can serve directly as effector cells through cytotoxicity for mononuclear phagocytes heavily infected with mycobacteria. Furthermore, in addition to the CD4+ T cell, gammadelta T cell receptor bearing T cells (gammadelta T cell, CD4-,CD8-) have been found to be a major reactive T cell population to M. tuberculosis. In studies supported by AI27243, we have demonstrated that gammadelta T cells are particularly reactive to live M. tuberculosis, which suggests that gammadelta T cells may play an important role in the innate or primary immune response to live intracellular organisms. These findings support a model of complementary roles for CD4+ and gammadelta T cells in the immune response to M. tuberculosis as follows. There are three specific aims to test this model: 1. To determine the mechanisms by which ingestion of live M. tuberculosis results in the induction of human gamma/delta T cells, by characterizing pathways of antigen-processing and requirements for MHC-like restriction elements, and by characterizing the role of mycobacterial viability and virulence. 2. To compare the antigenic repertoire and profiles of cytokines, likely to be involved in mononuclear phagocyte activation (IL-2,GM-CSF-TNF-alpha), of human CD4+ and gammadelta T cells reactive to M. tuberculosis. 3. To compare the functions of CD4+ and gammadelta T cells relative to mononuclear phagocytes infected with M. tuberculosis, in terms of cytotoxicity, phagocytosis and mycobacterial killing and to determine the role of the load of mycobacteria in the expression of these functions. The proposed studies will provide new insights into the relative and complementary roles of the two major reactive T cell populations, CD4+ and gammadelta T cells, in the human immune response to M. tuberculosis. An understanding of the T cell response to this pathogen will contribute to the design of improved methods of prevention and diagnosis of tuberculosis. This is a health related project.